Lung cancer is the leading cause of cancer death among African-Americans and this population has approximately 1/3 higher risk than Caucasians. Recently, collaborative studies that we and others have lead have identified regions on chromosomes 15q25, 5p15 and 6p21 that are highly significantly associated with lung cancer risk in Caucasians. The regions of association on chromosome 15q and 6p lie in areas of the genome that show very strong levels of linkage disequilibrium in Caucasians so that identifying the specific causal gene and causal variant(s) is problematic. In African- Americans, our preliminary study of the region on chromosome 15q25 shows a much more punctate pattern of linkage disequilbrium so that studies of the African-American population will provide a more precise localization of genetic variants. The preliminary data suggest the role of multiple genetic factors, but our initial studies conducted with a limited number of samples and SNPs are not yet sufficient to identify precisely the location(s) of causal variants. Our preliminary data show stronger effects on risks from SNPs on chromosomes 5p and 15q in African-Americans than in Caucasians. We therefore propose to genotype samples from three centers comprising over 1300 lung cancer cases and 1300 controls for 400 SNP loci in each of the three regions of interest. We will also genotype ancestry informative markers so that we can evaluate the ancestral background as a confounder. The first aim will perform dense SNP analysis in three genomic regions to sublocalize and characterize the impact on lung cancer risk in three genomic regions. The second aim will perform more detailed modeling to estimate joint effects of smoking, sex and genetic factors on lung cancer risk. This analysis will allow us to identify groups of African-American individuals at particularly higher risks for developing lung cancer.